This invention relates to compounds for the treatment of erectile dysfunction, including impotence. In particular, the invention relates to vasoactive compounds and their production, and treatments for impotence and the enhancement of sexual performance in men. The invention also includes a vehicle, delivery system and emulsifier for treating impotence.
Erectile dysfunction or impotence is characterized by the inability to achieve or maintain erection or tumescence of the penis. Impotence can be secondary to a wide variety of causes and may be physiological or psychological in origin. This condition is estimated to affect approximately 10-20 million American men chronically, but affects all men occasionally. For example, erection of the penis is inhibited in normal men due to anxiety, exertion or sexual disinterest. Sexual activity includes physical exertion and as men age, the inhibitory effects of exertion may overcome normal arousal mechanisms.
The etiology of chronic impotence may be psychogenic (32%), mixed psychogenic and organic (14%), organic (41%) or anatomical (13%). Organic causes include arterial insufficiency (27%), cavernous leakage (28%), neurological damage (13%), endocrinological defects (2.3%) and Peyronie""s disease (13.1%). Govier, F. E. Timing of Penile Color Flow Duplex Ultrasonography Using a Triple Drug Mixture. J. Urol, Vol. 153(5) (May 1995), pp.1472-1475. Thus, about 30% of all cases of impotence are primarily vascular in origin.
Compounds which produce or enhance arterial vasodilation or bring about cavernous vein constriction may be successful for the treatment of impotence. See U.S. Pat. Nos. 5,567,706 and 5,583,144, incorporated by reference. Similarly, compounds which counteract inhibitors of erection, such as catecholamines, may also contribute to effectiveness. Compounds which have been used in the pharmacological induction of erection were the vasodilator papaverine and the catecholamine antagonist, phenoxybenzamine. Such compounds may be administered by injection into the corpora cavernosa of the penis. Brindly, G. S. Cavernosal Alpha-blockage: A New Technique for Investigating and Treating Erectile Impotence, Br J. Psychiatry, Vol. 143 (1983), pp.332. These compounds are thought to work by mimicking the physiological mechanisms that relax penile smooth muscle.
Erection of the penis may be a self-perpetuating process of three steps: 1) vasodilation; 2) release of endogenous smooth-muscle relaxants; and 3) progression of these effects distal from the initial site of onset. This has been termed the xe2x80x9ccascade effectxe2x80x9d. According to this hypothesis, local induction of vasodilation in the corpus cavernosum may perpetuate itself into full erection of the penis whether or not the original vasodilator diffuses throughout the tissue. Where the concentration of vasoactive drug is highest, there is a local increase in blood flow, an activation of endothelium-mediated relaxing factors such as endothelium-derived nitric oxide, and an enlarging zone of regional smooth muscle relaxation. This xe2x80x9ccascadexe2x80x9d of a relaxation-inflow-relaxing effect can produce an erection. Support for this hypothesis is found in the observation that high doses of vasoactive drugs are required for erection in impotent patients with endothelial cell dysfunction, such as diabetes and hypercholesterolemia, presumably due to inability of these cells to produce vasodilators. The hypothesis is also supported by the observation that injected vasoactive drugs do not appear to uniformly diffuse from the injection site throughout the corpora of the penis, but are still capable of producing a full erection.
One of the first compounds used successfully for intracavernosal treatment of impotence is papaverine hydrochloride. Papaverine is an opium alkaloid and works as a smooth muscle relaxer possibly by cyclic GMP phosphodiesterase inhibition. It relaxes the musculature of the vascular system of the penis and increases blood flow. The effectiveness of papaverine hydrochloride injection depends on the dose, but has been reported to cause penile hematoma, elevated liver enzymes, priapism and lightheadedness in some patients, particularly if over-used. The free base of papaverine has been tried as a topical agent in the treatment of erectile dysfunction. In concentrations up to 20%, it was not sufficiently effective for clinical use. Kim, E. D. Papaverine Topical Gel Treatment For Erectile Dysfunction, Urology, Vol. 133(2)(1995), pp.361-365.
Another compound found effective in treating impotence is phentolamine hydrochloride or phentolamine methane sulfonate (phentolamine mesylate), described in U.S. Pat. No. 2,503,059 incorporated by reference. Phentolamine free base is a nonspecific alpha-adrenergic antagonist and has been successful in inducing penile erection, particularly when used in combination with papaverine. This combination was found to produce greater vasodilation of the arteries of the penis than either phentolamine or papaverine used alone.
Another compound found useful in the treatment of impotence is prostaglandin E1, a naturally occurring compound that acts to increase arterial inflow to the penis and may also restrict venous outflow. Prostaglandin E1 is preferred to other compounds used in injections for the treatment of impotence because it is metabolized locally in the penis and is less likely to cause systemic symptoms such as hypotension. Further, use of prostaglandin E1 has been found to result in a significantly lower incidence of penile hematomas from injections than either papaverine or phentolamine. However, prostaglandin E1 is considerably more expensive than other therapies and causes pain distal from the site of injection.
A synthetic form of prostaglandin E1, alprostadil USP (alprostadil), is a long-chain carboxylic acid with vasodilatory effects. Alprostadil acts to increase arterial inflow to the penis. In vitro studies have shown that alprostadil causes a dose-dependent smooth muscle relaxation in isolated corpus cavernosum and corpus spongiosum preparations. When used in vivo, it is thought that intraurethral alprostadil is absorbed from the urethra, transported throughout the erectile bodies of the penis by way of communicating vessels between the corpus spongiosum and corpus cavernosum, and induces vasodilation of the targeted vascular beds.
Various forms of alprostadil are available on the market, such as CAVERJECT (Upjohn, Kalamazoo, Mich.), which is an injectable form of alprostadil. Another form of alprostadil is MUSE (Vivus, Inc., Menlo Park, Calif.) which is a combination of alprostadil and polyethylene glycol. Intraurethral administration of MUSE has been reported to result in a substantial increase of cavernosal artery diameter and as much as a 10-fold increase in peak systolic flow velocities. Injections of alprostadil have been reported to cause pain, bleeding, hematomas and scar tissue leading to Peyronie""s Disease in some patients.
Urethral inserts or suppositories have been developed as an alternative to intracavernosal injection therapy. For example, U.S. Pat. No. 5,242,391, incorporated by reference, describes a device for the urethral insertion of a pellet containing alprostadil. The device has been reported to be effective about 65% of the time in doses of 125 to 1000 micrograms of alprostadil. However, urethral inserts do not appear to be as successful in treating impotence as intracavernosal injections.
The urethra is sensitive to irritants. There have been some reports that local anesthetic agents such as procaine and lidocaine can relieve some of the irritation upon intracavernosal injection. Schouman, M., Suppression of Prostaglandin E-1 Induced Pain By Dilution of the Drug With Lidocaine Before Intracavernosal Injection, J. Urology, Vol 148 (1992), pp.1266.
Androgenic steroids may also have a role in induction of erection, especially for patients with hypogonadism. Dihydrotestosterone has been administered transdermally, but has never been administered intraurethrally. Because dihydrotestosterone is fat-soluble, this may be a reasonable route of delivery. Tostain, J., Androgen Treatment of Erectile Dysfunction: When?How? Progres en Urologie, Vol. 7 (1997), pp.314-319.
Combinations of papaverine, phentolamine and alprostadil have been shown to be effective in treating impotence. For example, intracavernosal injections of this three-way combination, known as xe2x80x9ctri-mixxe2x80x9d, can be more effective in treating impotence with fewer side effects than papaverine, phentolamine or alprostadil used alone. Together, these compounds appear to act synergistically to increase arterial inflow, dilate sinusoidal smooth muscles, and restrict venous outflow, all promoting erectile activity with greater success and in smaller doses than single compound therapies. An example of a dosage combination for tri-mix is 10 micrograms of alprostadil, 500 micrograms of phentolamine and 15 mg of papaverine. Dosing of tri-mix preparations has not been standardized.
Agents for the formation of cationic liposomes are known to increase the solubility of substances they contain in cell membranes. Cationic phospholipids have been described for this purpose, such as phosphatidylethanolamine and phosphatidylcholine. Medium chain fats are useful for the solubilization of chemicals in membranes because they are both fat and water soluble. Therefore, diacylphosphatidylcholine, where the acyl groups are medium chain fats, may be especially efficacious as an emulsifier to aid the uptake of organic compounds by cell membranes. Dilauroylphosphatidylcholine has been disclosed as an ingredient in a composition to form cationic liposomes, for example, in U.S. Pat. No. 5,552,157, incorporated by reference. In the invention, cationic liposomes may form spontaneously when a composition as described is mixed with moisture from the urethra.
The effectiveness of compositions for the transurethral treatment of impotence depends largely on the chemical nature of the active ingredients and their ability to traverse cell membranes of the urethra and increase blood flow into the corpora cavernosa of the penis. An important factor is fat solubility, which allows diffusion across cell membranes. The invention provides compounds which can be used alone or together for the treatment of erectile dysfunction, particularly impotence. The invention is concerned with compounds that are useful in the treatment of impotence, particularly when delivered to the urethra. The compounds are formed as a complex or reaction product of components in which the lipophobic properties of one or more components are mitigated by formation of the compound. Formation of a compound, as opposed to a mixture of components, can be detected for example by NMR spectroscopy. Methods of making and using these compounds are also disclosed, as is an improved vehicle and delivery system.
The compounds of the invention each comprise a complex or reaction product of an anionic or negatively charged vasoactive or erection-inducing component and a cationic or positively charged vasoactive or erection-inducing component. These components are combined as acids and bases to form compounds which are believed to be organic salts or ionically bonded compounds. One or more compounds of the invention can be used in a composition for treating erectile dysfunction, with or without other ingredients. In a preferred composition, a compound of the invention is combined with a pharmaceutical vehicle and preferably includes an emulsifier. An emulsifier is provided to increase solubility in the mucous membrane of the urethra and can be a form of lecithin, or a compound of the general formula diacylphosphatidylcholine, where the xe2x80x9cacylxe2x80x9d portion might include any medium-to-long chain carboxylic acids of from six to twelve carbons in length. The preferred emulsifier is dilauroylphosphatidylcholine. A local anesthetic may also be included. Preferred anesthetics are lidocaine, also called xylocaine. Preferred compositions may also include more than one compound of the invention.
The compounds of the invention can be represented by the formula:
organic vasoactive cation++organic vasoactive anionxe2x88x92xe2x86x92organic vasoactive xe2x80x9csaltxe2x80x9d
The organic cation is selected from any of the following vasoactive compounds as the free base: phentolamine, papaverine, hydralazine, ketanserin, delquamine (delaquamine), n trazaodone, yohimbine, linsidomine, molsidomine, ifenprodil, piribedil, dipyramidole, minoxidil, phenoxybenzamine, prazosin, terazocin, doxazocin, sildenafil or moxisylyte (moxisylate), or local anesthetics such as procaine or lidocaine free base. The organic anion is selected from any of the following as free acids: vasoactive eicosanoids such as the free acid alprostadil (prostaglandin E1), prostaglandin E0, (13,14-dihydroprostaglandin E1), dinoprostone (prostaglandin E2), epoprostenol (prostacyclin, PGI2) and other prostaglandins; or other vasoactive anions such as nitroprusside.
One compound of the invention is a combination of alprostadil (an acid) and lidocaine (a base). Another compound of the invention is a combination of alprostadil and prazosin (a base). Each compound of the invention is believed to form as an ionically bonded salt of its acid and base components. The compounds have the surprising property of high solubility in drug delivery vehicles and lipids, and can easily diffuse across transitional epithelia cells of the urethra. Also, the compounds are benign and effective without undesirable side effects. In a preferred embodiment, compounds of the invention are formulated with an emulsifier, preferably dilauroylphosphatidylcholine, with or without a local anesthetic, such as lidocaine, also known as xylocaine.
The compounds and compositions of the invention can be administered by intraurethral injection or by application to the surface of the penis in the form of a topical composition or agent for transdermal delivery to the urethra.
The compounds and compositions of the invention provide improved solubility, and allow for self-adjusted dosage while preventing overdose problems. In one embodiment, a composition comprising a complex of alprostadil with each of lidocaine and prazosin provides for lower effective doses of alprostadil than in other therapies. This is thought to be achieved by increasing the absorption efficiency, by delivering the composition intraurethrally and by providing a more lipophillic composition which can cross membrane barriers more easily. Thus, alprostadil complexes with lidocaine to form the compound lidocaine alprostadilate. Alprostadil complexes with prazosin to form the compound prazosin alprostadilate.
Surprisingly, the new compounds have synergistic erection-inducing properties, and require significantly less alprostadil component than previously known intraurethral or multi-component intracavernosal therapies. The lidocaine and prazosin moieties are thought to provide an anesthetic effect and alpha-adrenergic blockage, respectively. Additionally, they each neutralize the acidity of alprostadil, rendering the resulting compounds, which can be thought of as salt complexes, fat soluble. Compositions of the invention, comprising one or more compounds formed as the reaction product of acid and base components having erection-inducing properties, have a neutral pH of about 6.0. Alprostadil is acidic, and known alprostadil compositions have an acid pH of about 4.5-5.2 (e.g. for various dosages of MUSE). Further, the anhydrous formulation of lidocaine alprostadilate and prazosin alprostadilate in the presence of an emulsifier, such as dilauroylphosphatidylcholine, ensures that the compounds remain at a neutral pH and in solution as an emulsion upon contact with the neutral aqueous environment of the urethra. The micro droplets which make up this emulsion may directly solubilize in the transitional epithelium of the urethra or the constituents may disassociate by an ion exchange process.
The active ingredients of the composition are provided at significantly lower concentrations than in the prior art. For example, preferred embodiments of the invention provide an effective amount of alprostadil, as lidocaine alprostadilate or prazosin alprostadilate, that can be one-tenth the concentration of alprostadil provided in the commercially available preparation known as MUSE. Consequently, even if compounds or compositions of the invention are self-administered beyond recommended dosage or schedule, the holding capacity of the human urethra will limit dosage to a safe amount. Further, in contrast to needle injections, which deposit the active drug at only one point, intraurethral administration allows diffusion across the urethral membrane all along the line of its path through the cavernosa. This may be another factor which explains why smaller doses of lidocaine and prazosin are effective at inducing erection intraurethrally in comparison to intracavernosally.